Scopus list of publications for June 11, 2023
DNAJB6 isoform specific knockdown: Therapeutic potential for limb girdle muscular dystrophy D1
(2023) Molecular Therapy – Nucleic Acids, 32, pp. 937-948.
Findlay, A.R.a , Paing, M.M.a , Daw, J.A.a , Haller, M.a , Bengoechea, R.a , Pittman, S.K.a , Li, S.b , Wang, F.b , Miller, T.M.a , True, H.L.c , Chou, T.-F.b , Weihl, C.C.a
a Department of Neurology, Neuromuscular Division, Washington University School of Medicine, Saint Louis, MO 63110, United States
b Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, United States
c Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8228, St. Louis, MO 63110, United States
Abstract
Dominant missense mutations in DNAJB6, a co-chaperone of HSP70, cause limb girdle muscular dystrophy (LGMD) D1. No treatments are currently available. Two isoforms exist, DNAJB6a and DNAJB6b, each with distinct localizations in muscle. Mutations reside in both isoforms, yet evidence suggests that DNAJB6b is primarily responsible for disease pathogenesis. Knockdown treatment strategies involving both isoforms carry risk, as DNAJB6 knockout is embryonic lethal. We therefore developed an isoform-specific knockdown approach using morpholinos. Selective reduction of each isoform was achieved in vitro in primary mouse myotubes and human LGMDD1 myoblasts, as well as in vivo in mouse skeletal muscle. To assess isoform specific knockdown in LGMDD1, we created primary myotube cultures from a knockin LGMDD1 mouse model. Using mass spectrometry, we identified an LGMDD1 protein signature related to protein homeostasis and myofibril structure. Selective reduction of DNAJB6b levels in LGMDD1 myotubes corrected much of the proteomic disease signature toward wild type levels. Additional in vivo functional data is required to determine if selective reduction of DNAJB6b is a viable therapeutic target for LGMDD1. © 2023 The Author(s)
Author Keywords
DNAJB6; isoform specific knockdown; limb girdle muscular dystrophy D1 (LGMDD1); morpholino; MT: Oligonucleotides: Therapies and Applications; proteomics
Funding details
17/932,996
MIFR20221004
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMS
Agricultural Research FoundationARFK08AR075894, K24AR073317, R01AR068797, R03AR081395
Document Type: Article
Publication Stage: Final
Source: Scopus
Sex-dependent effects of acute stress on amyloid-β in male and female mice
(2023) Brain: A Journal of Neurology, 146 (6), pp. 2268-2274.
Edwards, H.M.a , Wallace, C.E.a , Gardiner, W.D.a , Doherty, B.M.a , Harrigan, R.T.a , Yuede, K.M.a , Yuede, C.M.b , Cirrito, J.R.a
a Department of Neurology, Knight Alzheimer’s Disease Research Center, Hope Center for Neurological Disorders, St. Louis, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
The risk of developing Alzheimer’s disease is mediated by a combination of genetics and environmental factors, such as stress, sleep abnormalities and traumatic brain injury. Women are at a higher risk of developing Alzheimer’s disease than men, even when controlling for differences in lifespan. Women are also more likely to report high levels of stress than men. Sex differences in response to stress may play a role in the increased risk of Alzheimer’s disease in women. In this study, we use in vivo microdialysis to measure levels of Aβ in response to acute stress in male and female mice. We show that Aβ levels are altered differently between female and male mice (APP/PS1 and wild-type) in response to stress, with females showing significantly increased levels of Aβ while most males do not show a significant change. This response is mediated through β-arrestin involvement in Corticotrophin Releasing Factor receptor signalling pathway differences in male and female mice as male mice lacking β-arrestin show increase in Aβ in response to stress similar to females. © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Author Keywords
Alzheimer’s disease; corticotropin releasing factor; sexual dimorphism; stress; β-arrestin
Document Type: Article
Publication Stage: Final
Source: Scopus
Association of Stages of Objective Memory Impairment With Incident Symptomatic Cognitive Impairment in Cognitively Normal Individuals
(2023) Neurology, 100 (22), pp. E2279-E2289.
Grober, E.a , Petersen, K.K.b , Lipton, R.B.a , Hassenstab, J.a , Morris, J.C.a , Gordon, B.A.a , Ezzati, A.a
a Saul R. Korey, Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background and ObjectivesIncreasing evidence indicates that a subset of cognitively normal individuals has subtle cognitive impairment at baseline. We sought to identify them using the Stages of Objective Memory Impairment (SOMI) system. Symptomatic cognitive impairment was operationalized by a Clinical Dementia Rating (CDR) ≥0.5. We hypothesized that incident impairment would be higher for participants with subtle retrieval impairment (SOMI-1), higher still for those with moderate retrieval impairment (SOMI-2), and highest for those with storage impairment (SOMI-3/4) after adjusting for demographics and APOE ϵ4 status. A secondary objective was to determine whether including biomarkers of β-amyloid, tau pathology, and neurodegeneration in the models affect prediction. We hypothesized that even after adjusting for in vivo biomarkers, SOMI would remain a significant predictor of time to incident symptomatic cognitive impairment.MethodsAmong 969 cognitively normal participants, defined by a CDR = 0, from the Knight Alzheimer Disease Research Center, SOMI stage was determined from their baseline Free and Cued Selective Reminding Test scores, 555 had CSF and structural MRI measures and comprised the biomarker subgroup, and 144 of them were amyloid positive. Cox proportional hazards models tested associations of SOMI stages at baseline and biomarkers with time to incident cognitive impairment defined as the transition to CDR ≥0.5.ResultsAmong all participants, the mean age was 69.35 years, 59.6% were female, and mean follow-up was 6.36 years. Participants in SOMI-1-4 had elevated hazard ratios for the transition from normal to impaired cognition in comparison with those who were SOMI-0 (no memory impairment). Individuals in SOMI-1 (mildly impaired retrieval) and SOMI-2 (moderately impaired retrieval) were at nearly double the risk of clinical progression compared with persons with no memory problems. When memory storage impairment emerges (SOMI-3/4), the hazard ratio for clinical progression increased approximately 3 times. SOMI stage remained an independent predictor of incident cognitive impairment after adjusting for all biomarkers.DiscussionSOMI predicts the transition from normal cognition to incident symptomatic cognitive impairment (CDR ≥0.5). The results support the use of SOMI to identify those cognitively normal participants most likely to develop incident cognitive impairment who can then be referred for biomarker screening. © American Academy of Neurology.
Funding details
P01AG003991, P01AG026276, P30 AG066444, U19 AG024904, U19 AG032438
National Institutes of HealthNIH
National Institute on AgingNIA2PO1 AG003949, K23 AG063993
Alzheimer’s AssociationAA2019-AACSF-641329
Document Type: Article
Publication Stage: Final
Source: Scopus
Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity
(2023) PLoS Genetics, 19 (5), p. e1010760.
Yu, M.a , Ye, H.b , De-Paula, R.B.c , Mangleburg, C.G.d e , Wu, T.d e , Lee, T.V.b , Li, Y.b , Duong, D.f , Phillips, B.g h , Cruchaga, C.g h , Allen, G.I.i j , Seyfried, N.T.f , Al-Ramahi, I.d j k , Botas, J.c d j k , Shulman, J.M.a k b d j k
a Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
b Department of Neurology, Baylor College of Medicine, Houston, TX, United States
c Quantitative and Computational Biology Program, Baylor College of Medicine, Houston, TX, United States
d Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
e Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, United States
f Departments of Biochemistry and Neurology, Emory University School of Medicine, Atlanta, GA, United States
g Department of Psychiatry, Washington University, St. Louis, MO, United States
h Washington University, St. Louis, MO, United States
i Departments of Electrical and Computer Engineering, Computer Science, Statistics, Rice University, Houston, TX, United States
j Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, United States
k Center for Alzheimer’s and Neurodegenerative Diseases, Baylor College of Medicine, Houston, TX, United States
Abstract
Heterozygous variants in the glucocerebrosidase (GBA) gene are common and potent risk factors for Parkinson’s disease (PD). GBA also causes the autosomal recessive lysosomal storage disorder (LSD), Gaucher disease, and emerging evidence from human genetics implicates many other LSD genes in PD susceptibility. We have systemically tested 86 conserved fly homologs of 37 human LSD genes for requirements in the aging adult Drosophila brain and for potential genetic interactions with neurodegeneration caused by α-synuclein (αSyn), which forms Lewy body pathology in PD. Our screen identifies 15 genetic enhancers of αSyn-induced progressive locomotor dysfunction, including knockdown of fly homologs of GBA and other LSD genes with independent support as PD susceptibility factors from human genetics (SCARB2, SMPD1, CTSD, GNPTAB, SLC17A5). For several genes, results from multiple alleles suggest dose-sensitivity and context-dependent pleiotropy in the presence or absence of αSyn. Homologs of two genes causing cholesterol storage disorders, Npc1a / NPC1 and Lip4 / LIPA, were independently confirmed as loss-of-function enhancers of αSyn-induced retinal degeneration. The enzymes encoded by several modifier genes are upregulated in αSyn transgenic flies, based on unbiased proteomics, revealing a possible, albeit ineffective, compensatory response. Overall, our results reinforce the important role of lysosomal genes in brain health and PD pathogenesis, and implicate several metabolic pathways, including cholesterol homeostasis, in αSyn-mediated neurotoxicity. Copyright: © 2023 Yu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Document Type: Article
Publication Stage: Final
Source: Scopus
Efficacy of laser interstitial thermal therapy for biopsy-proven radiation necrosis in radiographically recurrent brain metastases
(2023) Neuro-Oncology Advances, 5 (1), art. no. vdad031, .
Chan, M.a , Tatter, S.a , Chiang, V.b , Fecci, P.c , Strowd, R.a , Prabhu, S.d , Hadjipanayis, C.e , Kirkpatrick, J.c , Sun, D.f , Sinicrope, K.f , Mohammadi, A.M.g , Sevak, P.f , Abram, S.h , Kim, A.H.i , Leuthardt, E.i , Chao, S.g , Phillips, J.h , Lacroix, M.j , Williams, B.k , Placantonakis, D.l , Silverman, J.l , Baumgartner, J.m , Piccioni, D.n , Laxton, A.a
a Wake Forest Baptist Health, Winston-Salem, NC, United States
b Yale School of Medicine, New Haven, CT, United States
c Duke University Medical Center, Durham, NC, United States
d University of Texas MD Anderson Cancer Center, Houston, TX, United States
e University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
f Norton Neuroscience Institute, Louisville, KY, United States
g Cleveland Clinic Lerner College of Medicine at CWRU, Cleveland, OH, United States
h Ascension St. Thomas Hospital West, Nashville, TN, United States
i Washington University School of Medicine, St. Louis, MO, United States
j Geisinger Medical Center, Danville, PA, United States
k University of Louisville Health, Louisville, KY, United States
l NYU Grossman School of Medicine, New York, NY, United States
m AdventHealth Medical Group, Orlando, FL, United States
n University of California San Diego Health, La JollaCA, United States
Abstract
Background: Laser interstitial thermal therapy (LITT) in the setting of post-SRS radiation necrosis (RN) for patients with brain metastases has growing evidence for efficacy. However, questions remain regarding hospitalization, local control, symptom control, and concurrent use of therapies. Methods: Demographics, intraprocedural data, safety, Karnofsky performance status (KPS), and survival data were prospectively collected and then analyzed on patients who consented between 2016-2020 and who were undergoing LITT for biopsy-proven RN at one of 14 US centers. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable Fine and Gray analysis, and Kaplan-Meier estimated survival. Results: Ninety patients met the inclusion criteria. Four patients underwent 2 ablations on the same day. Median hospitalization time was 32.5 hours. The median time to corticosteroid cessation after LITT was 13.0 days (0.0, 1229.0) and cumulative incidence of lesional progression was 19% at 1 year. Median post-procedure overall survival was 2.55 years [1.66, infinity] and 77.1% at one year as estimated by KaplanMeier. Median KPS remained at 80 through 2-year follow-up. Seizure prevalence was 12% within 1-month post-LITT and 7.9% at 3 months; down from 34.4% within 60-day prior to procedure. Conclusions: LITT for RN was not only again found to be safe with low patient morbidity but was also a highly effective treatment for RN for both local control and symptom management (including seizures). In addition to averting expected neurological death, LITT facilitates ongoing systemic therapy (in particular immunotherapy) by enabling the rapid cessation of steroids, thereby facilitating maximal possible survival for these patients. © 2023 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
Author Keywords
brain metastasis; Laser interstitial thermal therapy (LITT); radiation necrosis (RN); radiographic progression; stereotactic laser ablation (SLA)
Document Type: Article
Publication Stage: Final
Source: Scopus
Diffusion basis spectrum imaging as an adjunct to conventional MRI leads to earlier diagnosis of high-grade glioma tumor progression versus treatment effect
(2023) Neuro-Oncology Advances, 5 (1), .
Han, R.H.a , Johanns, T.M.b c , Roberts, K.F.d , Tao, Y.e , Luo, J.e , Ye, Z.f , Sun, P.f , Blum, J.f , Lin, T.-H.f , Song, S.-K.f , Kim, A.H.a c
a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
e Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
f Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Following chemoradiotherapy for high-grade glioma (HGG), it is often challenging to distinguish treatment changes from true tumor progression using conventional MRI. The diffusion basis spectrum imaging (DBSI) hindered fraction is associated with tissue edema or necrosis, which are common treatment-related changes. We hypothesized that DBSI hindered fraction may augment conventional imaging for earlier diagnosis of progression versus treatment effect. Methods: Adult patients were prospectively recruited if they had a known histologic diagnosis of HGG and completed standard-of-care chemoradiotherapy. DBSI and conventional MRI data were acquired longitudinally beginning 4 weeks post-radiation. Conventional MRI and DBSI metrics were compared with respect to their ability to diagnose progression versus treatment effect. Results: Twelve HGG patients were enrolled between August 2019 and February 2020, and 9 were ultimately analyzed (5 progression, 4 treatment effect). Within new or enlarging contrast-enhancing regions, DBSI hindered fraction was significantly higher in the treatment effect group compared to progression group (P =. 0004). Compared to serial conventional MRI alone, inclusion of DBSI would have led to earlier diagnosis of either progression or treatment effect in 6 (66.7%) patients by a median of 7.7 (interquartile range = 0-20.1) weeks. Conclusions: In the first longitudinal prospective study of DBSI in adult HGG patients, we found that in new or enlarging contrast-enhancing regions following therapy, DBSI hindered fraction is elevated in cases of treatment effect compared to those with progression. Hindered fraction map may be a valuable adjunct to conventional MRI to distinguish tumor progression from treatment effect. © 2023 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
Author Keywords
diffusion basis spectrum imaging; diffusion MRI; glioblastoma; pseudoprogression; radiation necrosis
Funding details
National Institutes of HealthNIHR01NS047592, R01NS116091, R25NS090978, U01EY025500
American Cancer SocietyACSPF-21-149-01-CDP
Alvin J. Siteman Cancer Center
Document Type: Article
Publication Stage: Final
Source: Scopus
Learning slopes in early-onset Alzheimer’s disease
(2023) Alzheimer’s and Dementia, .
Hammers, D.B.a , Nemes, S.a , Diedrich, T.a , Eloyan, A.b , Kirby, K.a , Aisen, P.c , Kramer, J.d , Nudelman, K.e , Foroud, T.e , Rumbaugh, M.e , Atri, A.f , Day, G.S.g , Duara, R.h , Graff-Radford, N.R.g , Honig, L.S.i , Jones, D.T.j k , Masdeu, J.C.l , Mendez, M.F.m , Musiek, E.n , Onyike, C.U.o , Riddle, M.p , Rogalski, E.q , Salloway, S.p , Sha, S.J.r , Turner, R.S.s , Weintraub, S.q , Wingo, T.S.t , Wolk, D.A.u , Wong, B.v , Carrillo, M.C.w , Dickerson, B.C.v , Rabinovici, G.D.d , Apostolova, L.G.a e x , the LEADS Consortiumy
a Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
b Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, RI, United States
c Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, United States
d Department of Neurology, University of California, San Francisco, CA, United States
e Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
f Banner Sun Health Research Institute, Sun City, AZ, United States
g Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
h Wien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami, FL, United States
i Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
j Department of Radiology, Mayo Clinic, Rochester, MN, United States
k Department of Neurology, Mayo Clinic, Rochester, MN, United States
l Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, TX, United States
m Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
n Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
o Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
p Department of Neurology, Alpert Medical School, Brown University, Providence, RI, United States
q Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
r Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, CA, United States
s Department of Neurology, Georgetown University, Washington, DC, United States
t Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
u Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
v Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
w Medical & Scientific Relations Division, Alzheimer’s Association, Chicago, IL, United States
x Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, IN, United States
Abstract
OBJECTIVE: Investigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without β-amyloid positivity. METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer’s Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined. RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric—the learning ratio (LR)—outperformed other learning slope calculations across analyses. CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses. Highlights: Learning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants. © 2023 the Alzheimer’s Association.
Author Keywords
early-onset Alzheimer’s disease; learning slopes; memory
Funding details
R56 AG057195
National Institute on AgingNIAP30 AG010124, P30 AG010133, P30 AG013854, P30 AG062421, P30 AG062422, P30AG066506, P50 AG005146, P50 AG005681, P50 AG008702, P50 AG023501, P50 AG025688, P50AG047366, U01 AG016976, U01AG6057195, U24AG021886
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Local translation in microglial processes is required for efficient phagocytosis
(2023) Nature Neuroscience, .
Vasek, M.J.a b , Mueller, S.M.a b , Fass, S.B.a b , Deajon-Jackson, J.D.a b , Liu, Y.a b , Crosby, H.W.a b , Koester, S.K.a b c , Yi, J.a b c , Li, Q.a d , Dougherty, J.D.a b
a Department of Genetics, Washington University School of Medicine, Saint Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
c Division of Biology and Biomedical Sciences, Washington University School of Medicine, Saint Louis, MO, United States
d Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO, United States
Abstract
Neurons, astrocytes and oligodendrocytes locally regulate protein translation within distal processes. Here, we tested whether there is regulated local translation within peripheral microglial processes (PeMPs) from mouse brain. We show that PeMPs contain ribosomes that engage in de novo protein synthesis, and these are associated with transcripts involved in pathogen defense, motility and phagocytosis. Using a live slice preparation, we further show that acute translation blockade impairs the formation of PeMP phagocytic cups, the localization of lysosomal proteins within them, and phagocytosis of apoptotic cells and pathogen-like particles. Finally, PeMPs severed from their somata exhibit and require de novo local protein synthesis to effectively surround pathogen-like particles. Collectively, these data argue for regulated local translation in PeMPs and indicate a need for new translation to support dynamic microglial functions. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
Funding details
National Institutes of HealthNIH
National Center for Advancing Translational SciencesNCATS
Center for Cellular Imaging, Washington UniversityWUCCIP30 CA91842, UL1TR002345
Document Type: Article
Publication Stage: Article in Press
Source: Scopus